THE CONTRIBUTION OF THE ENZYMES CYP2D6 AND CYP2C19 IN THE DEMETHYLATION OF ARTEMETHER IN HEALTHY-SUBJECTS

The contribution of the enzymes CYP2D6 and CYP2C19 to the metabolism o f artemether was evaluated in a cross-over study in seven healthy adul t Caucasian subjects. The pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin were compared when given 100 mg artemether orally alone or in combination with either CYP2D6-inhib itor quinidine or CYP2C19-inhibitor omeprazole. Plasma concentrations of artemether and dihydroartemisinin were measured with reversed phase high performance liquid chromatography with electro-chemical detectio n (HPLC-ED). Artemether was rapidly absorbed with a mean t(max) of 0.8 h (95% confidence interval, CI = 0.5-1.1) reaching a mean C-max of 29 ng/ml (14-45 ng/ml). The mean elimination half-life was 1.3 h (0.8-1. 8 h). The pharmacokinetic parameters for dihydroartemisinin were not s ignificantly different from those for artemether. Artemether combined with quinidine revealed no significant changes in the plasma concentra tions of either artemether or dihydroartemisinin. No changes were seen in the combination with omeprazole as a CYP2C19 inhibitor. A second p eak in the plasma concentration profile was observed 2-4 h after drug intake. This phenomenon was possibly related to variable gastric empty ing. No major contribution of the enzymes CYP2D6 or CYP2C19 was found in artemether metabolism. No interethnic differences in artemether met abolism on the basis of a genetic polymorphism of these enzymes is to be expected.